AIIogeneic hematopoietic cell transplantation (HCT) using non-myeloablative conditioning with 200 cGy total body irradiation +/- fludarabine combined with postgrafting immunosuppression by mycophenolate mofetil and cyclosporine allows reliable engraftment of HLA identical sibling grafts in patients with a variety of hematologic malignancies. This extends the benefits of allografting (graft-vs-tumor [GVT] effects and replacement of marrow function) to older patients or those with medical conditions that preclude conventional high-dose conditioning, all with a lower non-relapse mortality (NRM). This approach shifts the burden of anti-tumor activity from the cytotoxic agents to the GVT and graft-vs-host immune responses. These responses take time to develop, and are more successful in patients with diseases that are either slow growing or whose burden has been reduced by prior therapy. We have used the anti-tumor effects of preceding high dose autologous HCT to reduce disease burden and allow time for GVT effects to eliminate residual disease. This two-step approach may provide curative therapy to elderly patients with non-Hodgkin lymphoma (NHL) and myeloma (MM). Our hypothesis in Aim 1 is that tandem auto/allo transplants will allow allogeneic HCT to achieve better tumor control and lower NRM than conventional allografting, and this may be extended to older patients. For MM patients, we hypothesize that results will be superior to tandem autologous transplants. Our preliminary experience with 54 MM patients, median age of 54 years, has shown 79% survival with a median follow-up of 18 months and forms the basis for a national trial. When autografts are not possible for MM patients, we will evaluate the addition of intermediate dose melphalan to the allogeneic HCT protocol in Aim 2. Aim 3 will explore the inclusion of newer agents with greater tumor specificity combined with non-myeloablative HCT for control of disease in patients with NHL (radiolabeled anti-CD20 antibody), Hodgkin's Disease (chimeric anti-CD30 antibody) and Philadelphia chromosome positive acute lymphocytic leukemia (STI-571). These approaches will further advance the use of potentially curative allogeneic GVT therapy to patients with B cell malignancies.